How the neonatal immune system avoids inflammatory responses during initial acquisition of the microbiota remains unclear. Establishing intestinal homeostasis is particularly challenging for neonates because their immune systems have not fully developed. The goal of this application is to investigate how maternal antibodies instruct the neonatal immune system to limit T cell responses to newly acquired microbial antigens in the intestine. This proposal builds on our discovery that mothers generate T cell-independent IgG2b and IgG3 antibodies reactive with the microbiota and pass these antibodies to their offspring in utero and through breastmilk. Newborn mice that do not receive any maternal antibodies show increased translocation of commensal bacteria across the intestinal barrier, mount inappropriate T cell responses against mucosal antigens, and weigh less for the first few weeks of life. Similar defects are apparent in neonates that only lack maternal IgG2b and IgG3, demonstrating that these isotypes are required to maintain intestinal homeostasis early in life. Remarkably, if neonates are experimentally forced to acquire T-dependent IgG2c antibodies reactive with the microbiota, then they suffer significant mortality and morbidity. Thus, our preliminary results indicate that the type of antibody acquired by neonates from their mothers can dramatically impact health during the first weeks of life. This proposal will determine the mechanism by which different IgG isotypes suppress or enhance responses to the microbiota in neonates. In addition, we will determine whether specific bacteria drive the immune dysregulation observed in the absence of maternal IgG antibodies or when inflammatory IgG isotypes are acquired. Overall, the studies described in this proposal will reveal how microbiota-reactive maternal antibodies regulate neonatal immunity to the microbiota.